Management of patients after total knee arthroplasty using mechanical prophylaxis and reduced doses of edoxaban: A retrospective cohort study.

OBJECTIVE: Edoxaban is given as pharmacologic prophylaxis alone or in combination with mechanical prophylaxis for venous thromboembolism after total knee arthroplasty. Several choices are made regarding edoxaban dosages when used in combination with mechanical prophylaxis. This study aimed to compare efficacy and safety in patients who received edoxaban with elastic stockings after total knee arthroplasty between those who received the standard dose, including those who received a reduced dose after meeting dose reduction criteria, and those who received reduced doses without dose reduction criteria. MATERIALS AND METHODS: This study included 143 patients in the standard-dose group (with 125 patients receiving dose-adjusted edoxaban 15 mg/day) and 110 patients in the low-dose group, and it compared the incidence of venous thromboembolism and bleeding events between groups. The impact of edoxaban administration on the occurrence of venous thromboembolism after total knee arthroplasty was also examined using multivariate regression analysis. RESULTS: Our results showed that rates of venous thromboembolism and bleeding events in patients wearing elastic stockings after total knee arthroplasty were similar in both standard- and low-dose groups. Multivariate regression analysis showed that use of reduced-dose edoxaban without dose adjustment did not correlate with the occurrence of venous thromboembolism, but edoxaban administration was significantly associated with older age and longer surgery time (odds ratio 1.84, 95% confidence interval 1.04 - 3.25, p = 0.036; odds ratio 1.69; 95% confidence interval 1.09 - 2.62, p = 0.019). CONCLUSION: These results suggest that reduced dose selection of edoxaban for patients who receive mechanical prophylaxis after total knee arthroplasty and post-administration pharmacological management may be useful.

Olanzapine treatment effectively relieves breakthrough chemotherapy-induced nausea and vomiting: a real-world experience.

BACKGROUND: Olanzapine treatment prevents chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC). However, its role in the secondary prevention of breakthrough CINV in real-world cancer care should be further evaluated. METHOD: We conducted a retrospective study on patients receiving olanzapine to prevent breakthrough CINV refractory to standard antiemetic therapy. The major outcome was improvement in CINV, defined as any downgrade in CINV symptoms, according to the Common Terminology Criteria for Adverse Events. Comprete response was defined as no symptoms in CINV, i.e., Grade 0. These outcomes were compared in the HEC versus non-HEC groups and the standard- (5 or 10 mg/day) versus low- (2.5 mg/day) dose groups. The other outcome measurement was adverse events (AEs). RESULTS: We analyzed 127 patients, including 92 women, with a median age of 50 years (range: 19-89 years). Baseline CINV severity was grade 1, 2, and 3 in 18%, 69%, and 13% of the patients, respectively. After prophylaxis with olanzapine at doses of 2.5, 5, or 10 mg/day, improvement was observed in 105 (83%) patients, with a complete response in 42 patients (33%). The improvement and complete remission rates for the HEC (n = 96) and non-HEC (n = 31) groups were 86% and 71% (p = 0.048) versus 38% and 19% (p = 0.062), respectively. The rates for the standard- (n = 98) and low- (n = 29) dose groups were 86% and 82% (p = 0.568) versus 28% and 52% (p = 0.015), respectively. Thirty-four patients (27%) experienced olanzapine-related AEs, mainly somnolence (n = 28). Grade 3 or higher AEs were not observed. CONCLUSION: Our study results support the clinical application of olanzapine for the secondary prevention of breakthrough CINV.

Effects of reduced edoxaban administration on bleeding risk and D-dimer levels in patients wearing elastic stockings after total hip arthroplasty: A retrospective cohort study.

OBJECTIVE: Edoxaban is sometimes given at reduced doses when used concomitantly with physical prophylaxis to prevent symptomatic venous thromboembolism (VTE) after total hip arthroplasty (THA). This study aimed to evaluate the safety of reduced doses of edoxaban administered independent of the dose-reduction criteria and their effects on D-dimer levels after THA in Japanese patients. MATERIALS AND METHODS: This study enrolled 22 patients who received edoxaban 30 mg/day and 45 patients who received edoxaban 15 mg/day with dose adjustment as a standard-dose group, and 110 patients who received edoxaban 15 mg/day without dose adjustment as a low-dose group. The incidence of bleeding events was then compared between groups with patients wearing elastic stockings. Multivariate regression analysis was also performed to examine the effect of edoxaban administration on D-dimer levels after THA. RESULTS: The incidence of bleeding events after THA did not differ significantly between groups. In the multivariate model, dose reduction of edoxaban did not correlate with D-dimer levels on postoperative days 7 and 14, but higher D-dimer levels at postoperative days 7 and 14 correlated significantly with longer duration of surgery (odds ratio (OR) 1.66, 95% confidence interval (CI) 1.20 - 2.29, p = 0.002; OR 1.63, 95% CI 1.17 - 2.29, p = 0.004, respectively). CONCLUSION: These results suggest that information on the duration of surgery may be useful in the pharmaceutical management in edoxaban drug prophylaxis combined with physical prophylaxis after THA in Japanese patients.

Elevated INR in a COVID-19 patient after concomitant administration of favipiravir and warfarin: A case report.

WHAT IS KNOWN AND OBJECTIVE: Favipiravir is a promising treatment candidate for managing coronavirus disease 2019 (COVID-19). Warfarin has many drug interactions, but no interactions with favipiravir have been reported. CASE SUMMARY: Our patient was taking warfarin for deep vein thrombosis. The international normalized ratio (INR) was stable (1.65 to 2.0); however, it increased to 4.63 after administering favipiravir. The patient had no other factors justifying this change. WHAT IS NEW AND CONCLUSION: Favipiravir and warfarin might have previously unidentified drug interactions that elevated the INR. Therefore, INR must be closely monitored when they are concomitantly administered in COVID-19 patients.

Validation of Self-Monitoring Devices Supporting Sodium Intake Reduction: An Experimental Feeding Study Using Standardized Low-Salt and High-Salt Meals among Healthy Japanese Volunteers.

INTRODUCTION: Although several approaches for approximating daily Na intake and the Na/K ratio using casual urine are available, the most useful method remains unclear during daily practice and at home. METHODS: Twenty-seven participants measured their casual urinary Na/K ratio repeatedly using a Na/K ratio monitor and also measured overnight urine once daily using a monitoring device which delivers on-site feedback to estimate their salt intake under unrestricted, low-salt (LS) (6 g/day), and high-salt (HS) (12 g/day) diets. RESULTS: The monitoring method utilizing overnight urine to estimate daily Na remained insensitive, resulting in significant overestimation during the LS diet and underestimation during the HS diet periods; estimated salt intake during the LS and HS diet periods plateaued at 7-8 g/day and 9-10 g/day within 3 day; mean estimated salt intake was 11.3 g/day, 7.9 g/day, and 9.8 g/day on the last day of the unrestricted, LS, and HS diets; the coefficient of variation (CV) of the estimated Na intake was 0.23 and 0.17 in the latter half of the low- and high-salt diet periods, respectively. The mean urinary Na/K molar ratio was 5.6, 2.5, and 5.3 on the last day of the unrestricted, LS, and HS diets; the CV of the daily mean Na/K ratio was 0.41 and 0.36 in the latter half of the LS and HS diet periods, respectively. The urinary Na/K ratio during the LS and HS diet periods plateaued within 2 days. The monitoring method based on the daily mean of the casual urinary Na/K ratio reflected the actual change in Na intake, and the estimated value tracked the actual changes in salt intake with smaller difference than the overnight urine estimates when using the estimation coefficient set at 2; estimated salt intake during the LS and HS diet periods plateaued at 5-6 g/day and 10-12 g/day within 2-3 day; mean estimated salt intake was 11.0 g/day, 5.7 g/day, and 10.7 g/day on the last day of the unrestricted, LS, and HS diets, respectively. DISCUSSION/CONCLUSION: Estimates of daily Na intake derived from overnight urine may remain insensitive during dietary interventions. The urinary Na/K ratio reflects the actual change in Na intake during dietary modification and may serve as a practical marker, particularly during short-term interventions. Conversion from the urinary Na/K ratio to estimated salt intake may be useful, if the coefficient was set appropriate by further investigations.

[Effect of Storage of Tulobuterol Tapes after Package Opening and Liner Peeling on Their Formulation Properties].

Although tulobuterol tape is provided to patients in an inner package, information regarding the stability of the tape after opening the packaging may be requested by patients. This study was performed to generate underlying data on the storage stability after package opening or liner peeling with package opening. Tulobuterol tapes were stored at 25℃, 60% relative humidity (RH); 40℃, 75%RH; or in a refrigerator (2-4℃, 10-30%RH) for 1 day or 3 days. In a peel adhesive strength test after package opening, storage at 25℃, 60%RH had a low effect on the adhesive strength of the tape. Storage after liner peeling with package opening resulted in variable adhesive strength of the tape. Regarding drug release properties, for storage after package opening, the f2 values of tapes stored in the three different conditions were over 50, except for tapes stored at 25℃, 60%RH for 3 days. For the tapes stored at 25℃, 60%RH or 40℃, 75%RH after liner peeling with package opening, the release rate and the ratio of drug released at 24 h may be decreased because the drug content decreased due to drug sublimation. This study suggested that tulobuterol tapes can be stored after package opening at 25℃, 60%RH for 1 d.

[Assessment of the Relationship between Hypnotics and Delirium Using the Japanese Adverse Drug Event Report (JADER) Database].

　The Japanese Adverse Drug Event Report (JADER) database was used to examine the risk of delirium and the time of its onset with various hypnotics, including 10 benzodiazepines (BZDs), 3 non-benzodiazepines (non-BZDs), 1 melatonin receptor agonist (MRTA), and 1 orexin receptor inhibitor (OXRI). Data entered in the JADER database between April 1, 2004 and February 1, 2016 were analyzed. The index for safety signal detection, the reporting odds ratio (ROR), was the odds ratio for adverse drug reaction reporting. The ROR for each drug was calculated; a signal was considered present if the lower bound of the 95% confidence interval of the ROR was greater than 1. The time to onset of delirium was calculated for drugs for which the number of days from the start of drug administration to delirium onset was reported. During the period examined in the analysis, a total of 621114 adverse drug reaction reports were seen, and the total number of delirium reports was 1417 after redundant cases were excluded. A signal was detected for 5 of the 10 BZDs and all 3 non-BZDs, with no signal for the MRTA and the OXRI. The time of delirium onset varied widely even for drugs classified as being in the same action duration group, and no correlation was seen for delirium onset time. The results of this study suggested that delirium risk varies depending on the hypnotic. Thus, hypnotics can be selected according to their delirium risk.

Prevalence of Therapeutic Drug Monitoring for Lithium and the Impact of Regulatory Warnings: Analysis Using Japanese Claims Database.

BACKGROUND: Therapeutic drug monitoring (TDM) for lithium is recommended in guidelines; however, the prevalence of TDM for lithium is seldom reported. We have therefore investigated the prevalence of TDM for lithium and evaluated the impact of the regulatory warnings requiring routine TDM for lithium. METHODS: Monthly claims data covering around 1.7 million persons aged 20-74 years old during the period January 1, 2005, and March 31, 2015, were evaluated. All patients who had at least one prescription for lithium were selected and included to calculate the annual prevalence of TDM for lithium. Also we assessed whether the 2 regulatory warnings requiring routine TDM for lithium and issued in April 2012 and September 2012 had an impact on TDM for lithium, using segmented regression analysis. RESULTS: Between 2005 and 2014, 136,956 prescriptions of lithium were issued to 5823 patients, and the annual prevalence of TDM for lithium was 14.9% (95% confidence interval, 14.7%-15.1%). The analysis revealed that the mean prevalence increased abruptly by 6.9% (P = 0.001) after the regulatory warning in April 2012, whereas that the warning in September 2012 decreased by 1.2% (P = 0.47). There was no significant change in trends of period prevalence after the warning in April 2012 (April 2012-August 2012) compared with prevalence before the warning (April 2010-March 2012). Similarly, no significant change was observed in the trends before (April 2012-August 2012) and after (September 2012-March 2014) the subsequent warning in September 2012. CONCLUSIONS: Results showed that the prevalence of TDM for lithium was low, although TDM for lithium was strongly recommended by the guidelines. Regulatory warnings requiring compliance with the measurement of blood levels during treatment with lithium, issued twice during the five-month period, were associated with an increase in the prevalence of TDM for lithium. However, the impact of the second warning was not remarkable compared with the first warning.

Utilization of the Bridging Strategy for the Development of New Drugs in Oncology to Avoid Drug Lag.

Global trial (GT) strategy and bridging (BG) strategy are currently the main clinical development strategies of oncology drugs in Japan, but the relationship between development style and drug lag and how the bridging strategy has contributed to the solution of drug lag have not been clear. We investigated the potential factors that influenced submission lag (SL), and also compared the differences in SL among early-initiation BG strategy, late-initiation BG strategy, and GT strategy. A stepwise linear regression analysis identified the potential factors that shorten SL: development start lag and development style. Comparison of the differences in SL among the strategies also indicated that the SL in the GT strategy and that in the early-initiation BG strategy were significantly shorter than that in the late-initiation BG strategy. The findings in our study suggest that the late-initiation BG strategy may not contribute to shortening drug lag. Because the number of late-initiation BG studies has not decreased, we propose first that pharmaceutical companies should initiate clinical development as early as possible in Japan so that they can choose the GT strategy as a first option at the next step, and second when they cannot choose the GT strategy after investigating differences in exposure between Japanese and non-Japanese in a phase 1 study, they should select the early BG strategy to avoid future drug lag. It is also important for the regulatory authorities to provide reasonable guidance to have a positive impact on strategic decisions, even for foreign-capital companies.

Effect of high-potency statins on HbA1c in patients with or without diabetes mellitus.

BACKGROUND: The increased risk of new-onset diabetes with statin use, including high-potency statins, is well known. However, the effects of high-potency statins on HbA1c are unclear. A retrospective cohort study was conducted to examine the effect of high-potency statins on HbA1c in patients with or without diabetes. The study enrolled new statin users identified via the electronic healthcare database of the general hospital in Japan. METHODS: Following identification of all individuals (n = 4,672) who had been prescribed a lipid lowering drug at least once between January 1, 2010 and July 31, 2014, new statin users were selected (n = 1,136). Patients were excluded if they had been prescribed treatment with a statin within the preceding 6-month period. HbA1c levels before and during high-potency statin treatment were compared using the dependent t-test. In addition, the hazard ratio for the incidence of diabetes with high-potency statin treatment was estimated, using low-potency statins as a reference. RESULTS: In patients with diabetes (n = 153), mean HbA1c (%) levels significantly increased by 0.4 % after high-potency statin use (7.57 ± 1.58; p = 0.0002) compared to baseline (7.18 ± 1.37). Similarly, HbA1c (%) levels significantly increased from 5.78 ± 0.38 to 5.92 ± 0.45 (p < 0.0001) after high-potency statin use in patients without diabetes (n = 165). Furthermore, a trend toward an increase in HbA1c was found for all of the high-potency statins irrespective of a history of diabetes. CONCLUSIONS: The use of high-potency statins may increase HbA1c levels in patients with or without diabetes.

Comparative effect of clopidogrel plus aspirin and aspirin monotherapy on hematological parameters using propensity score matching.

BACKGROUND: Clopidogrel and aspirin are antiplatelet agents that are recommended to reduce the risk of recurrent stroke and other cardiovascular events. Dual antiplatelet therapy with clopidogrel and aspirin has been shown to increase the risk of hemorrhage, but the effects of the drugs on laboratory parameters have not been well studied in real-world clinical settings. Therefore, we evaluated and compared the effects of combination therapy with clopidogrel plus aspirin and aspirin monotherapy on laboratory parameters. METHODS: We used data from the Nihon University School of Medicine Clinical Data Warehouse obtained between November 2004 and May 2011 to identify cohorts of new users (n = 130) of clopidogrel (75 mg/day) plus aspirin (100 mg/day) and a propensity score matched sample of new users (n = 130) of aspirin alone (100 mg/day). We used a multivariate regression model to compare serum levels of creatinine, aspartate aminotransferase, and alanine aminotransferase, as well as hematological parameters including hemoglobin level, hematocrit, and white blood cell, red blood cell, and platelet counts up to 2 months after the start of administration of the study drugs. RESULTS: There were no significant differences for any characteristics and baseline laboratory parameters between users of clopidogrel plus aspirin and users of aspirin alone. Reductions in white blood cell and red blood cell counts, hemoglobin levels, and hematocrit in users of clopidogrel plus aspirin were significantly greater than those in users of aspirin alone. CONCLUSION: Our findings suggest that adverse hematological effects may be greater with combination clopidogrel plus aspirin therapy than with aspirin monotherapy.

[Adhesion loss of syrups in a metering glass which consists of a low surface free energy material].

We previously reported a strong positive correlation between syrup viscosity and the rate of syrup loss due to adhesion to a glass metering device. In this study, we examined differences in the surface free energies of metering devices made of different polymeric materials, since reducing adhesion loss to metering devices could improve the efficiency of drug preparation involving highly viscous syrups. Among metering devices made of glass only, glass with a silicone coating (SLC), polypropylene (PP), and polymethylpentene (PMP) the surface free energy of the glass-only metering device was the highest (49.2 mN/m). The adhesion loss obtained for highly viscous syrups in the PP and PMP metering devices was significantly lower than that of the glass metering device. Measurements of syrup contact angles suggested that in metering devices made of PP and PMP, which have low surface free energies, a decrease in the spreading wetting of syrups was a factor in reducing the rate of adhesion loss. Thus irrespective of the syrup viscosity being measured, metering devices produced from materials with low surface free energies can reduce the time required to prepare prescriptions without compromising the accuracy of drug preparation.

Effect of beta-cyclodextrin on the degradation rate of amoxicillin in acidic solution.

The formation of an inclusion complex of amoxicillin (AMX) with beta-cyclodextrin (beta-CD) in aqueous solution was confirmed by a solubility method and proton nuclear magnetic resonance (1H-NMR) spectroscopy. The apparent stability constant for the inclusion complex was 10.72 M(-1) in water at 25 degrees C. The effect of alpha-CD, beta-CD, and gamma-CD on the degradation of AMX in a pH 1.2 solution at 37 degrees C was investigated. beta-CD and gamma-CD reduced the rate of degradation. alpha-CD had no effect. These results were consistent with those of 1H-NMR spectroscopy. The effect of beta-CD on the degradation rate was studied in more detail. The apparent first order rate constant for the degradation of AMX in the pH 1.2 solution at 37 degrees C was 0.1121 h(-1) (t(1/2)=6.18 h), which decreased with the addition of beta-CD. The rate constants and t(1/2) values for the concentrations of beta-CD added, corresponding to molar ratios of AMX to beta-CD of 1:0.5, 1:1, 1:2, 1:5, and 1:10, were 0.1051 h(-1) and 6.59 h, 0.0992 h(-1) and 6.98 h, 0.0893 h(-1) and 7.76 h, 0.0697 h(-1) and 9.95 h, and 0.0509 h(-1) and 13.61 h, respectively. The activation energy for the degradation of AMX in the pH 1.2 solution was increased from 6.9 x 10(4) J/mol (AMX alone) to 8.0 x 10(4) J/mol (AMX:beta-CD=1:10).

Involvement of an influx transporter in the blood-brain barrier transport of naloxone.

Naloxone, a potent and specific opioid antagonist, has been shown in previous studies to have an influx clearance across the rat blood-brain barrier (BBB) two times greater than the efflux clearance. The purpose of the present study was to characterize the influx transport of naloxone across the rat BBB using the brain uptake index (BUI) method. The initial uptake rate of [(3)H]naloxone exhibited saturability in a concentration-dependent manner (concentration range 0.5 microM to 15 mM) in the presence of unlabeled naloxone. These results indicate that both passive diffusion and a carrier-mediated transport mechanism are operating. The in vivo kinetic parameters were estimated as follows: the Michaelis constant, K(t), was 2.99+/-0.71 mM; the maximum uptake rate, J(max), was 0.477+/-0.083 micromol/min/g brain; and the nonsaturable first-order rate constant, K(d), was 0.160+/-0.044 ml/min/g brain. The uptake of [(3)H]naloxone by the rat brain increased as the pH of the injected solution was increased from 5.5 to 8.5 and was strongly inhibited by cationic H(1)-antagonists such as pyrilamine and diphenhydramine and cationic drugs such as lidocaine and propranolol. In contrast, the BBB transport of [(3)H]naloxone was not affected by any typical substrates for organic cation transport systems such as tetraethylammonium, ergothioneine or L-carnitine or substrates for organic anion transport systems such as p-aminohippuric acid, benzylpenicillin or pravastatin. The present results suggest that a pH-dependent and saturable influx transport system that is a selective transporter for cationic H(1)-antagonists is involved in the BBB transport of naloxone in the rat.

Enhancement of water solubility of fullerene by cogrinding with mixture of cycloamyloses, novel cyclic alpha-1,4-glucans, via solid-solid mechanochemical reaction.

Improvement of solubility for fullerene (C60) was studied by cogrinding with cycloamyloses using a ball mill in the solid state. Cycloamylose is a novel cyclic alpha-1,4-glucan produced from synthetic amylose by enzymatic reaction. Although sample solutions showed a pale yellow for the initial period of cogrinding with cycloamyloses and C60, the color varied to brown after 48 h. Subsequently, the solubility of C60 was improved markedly to 560 (microg/ml) at 96 h. From powder X-ray diffraction analysis, the peak intensity of crystalline C60 decreased as the cogrinding time was extended. The UV-VIS absorption spectrum of C60 shows absorption bands at 262 and 340 nm in water with cycloamyloses, and 258 and 328 nm in n-hexane. These results suggested that C60 molecules were dispersed into cycloamyloses micellar system and the red-shift of the UV-VIS spectra was due to an intermolecular interaction between C60 and cycloamyloses.